Decreased Skeletal Muscle Intramembrane Charge Movement And Contractile Activation In S100A1 Knock Out Mice

Abstract

S100A1, a calcium binding protein expressed in skeletal and cardiac muscle, modulates Ca2+ signaling. We have previously shown that isolated flexor digitorum brevis (FDB) skeletal muscle fibers from S100A1 knock out (ko) mice exhibit reduced Ca2+ transients with delayed onset in response to single action potentials compared to wild type (wt) FDB fibers (Prosser et al, 2008). Utilizing the potentiometric dye di-8-ANEPPS, we now show no differences in action potential properties between wt and ko fibers. Using whole cell voltage clamp of single isolated fibers we examined surface and transverse tubule membrane electrical properties in wt and ko fibers. Preliminary non-linear capacitive current measurements indicate that maximum charge moved (Qmax) is less in ko than wt fibers (wt Qmax = 43.6 ± 3.4 nC/μF, ko Qmax = 32.0 ± 3.5 nC/μF; p < .05). The temporally delayed, steeply voltage dependent component of intramembrane charge movement at intermediate depolarizations (Qγ) is less pronounced in ko than in wt fibers, consistent with a steeper voltage dependence of charge moved (wt k = 7.2 ± .5, ko k = 10.8 ± 1.2, p < .05). The midpoint voltage of charge moved was not different (wt Vhalf = -26.1 ± 2.8 mV, ko Vhalf = -28.5 ± 1.5 mV). Both the amplitude and the voltage dependence of Cav1 Ca2+ currents were similar in wt and ko fibers. In vivo maximal specific force (force normalized to muscle mass) was significantly decreased in ko compared with wt muscles (wt Po = 1.52 ± .09 g/mg, ko Po = 1.11 ± .09 g/mg; p < .05). These results are consistent with muscles lacking S100A1 having decreased charge moved during membrane depolarization, causing depressed SR Ca2+ release, and ultimately decreased force generation.